Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

被引：98

作者：

Greene, Chris ^{[1
]}

Hanley, Nicole ^{[1
]}

Reschke, Cristina R. ^{[2
,3
]}

Reddy, Avril ^{[1
]}

Mae, Maarja A. ^{[4
]}

Connolly, Ruairi ^{[2
,5
,6
]}

Behan, Claire ^{[2
,5
,6
]}

O'Keeffe, Eoin ^{[1
]}

Bolger, Isobel ^{[1
]}

Hudson, Natalie ^{[1
]}

Delaney, Conor ^{[1
]}

Farrell, Michael A. ^{[7
]}

O'Brien, Donncha F. ^{[8
]}

Cryan, Jane ^{[7
]}

Brett, Francesca M. ^{[7
]}

Beausang, Alan ^{[7
]}

Betsholtz, Christer ^{[4
]}

Henshall, David C. ^{[2
,9
]}

Doherty, Colin P. ^{[2
,5
,6
]}

Campbell, Matthew ^{[1
,2
]}

机构：

[1] Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland

[2] Univ Med & Hlth Sci, Sci Fdn Ireland Res Ctr Chron & Rare Neurol Dis, Royal Coll Surg Ireland, FutureNeuro, Dublin, Ireland

[3] RCSI Univ Med & Hlth Sci, Sch Pharm & Biomol Sci, Dublin 2, Ireland

[4] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden

[5] St James Hosp, Dept Neurol, Hlth Care Ctr, Hosp 5, Dublin 8, Ireland

[6] Trinity Coll Dublin, Biomed Sci Inst, Acad Unit Neurol, Room 5-41, Dublin 2, Ireland

[7] Beaumont Hosp, Dept Neuropathol, Dublin, Ireland

[8] Beaumont Hosp, Dept Neurosurg, Dublin, Ireland

[9] RCSI Univ Med & Hlth Sci, Dept Physiol & Med Phys, Dublin 2, Ireland

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

欧洲研究理事会; 爱尔兰科学基金会;

关键词：

P-GLYCOPROTEIN; EPILEPSY; EXPRESSION; RESISTANCE; ADHESION; MODEL; PERMEABILITY; DISRUPTION; DAMAGE;

D O I：

10.1038/s41467-022-29657-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.

引用

页数：13

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